Identification of vascular disruptor compounds by analysis in zebrafish embryos and mouse embryonic endothelial cells

- Vascular disruptor compounds (VDCs) were identified through screening in zebrafish embryos and mouse C166 cells.
- In zebrafish, exposure to VDCs caused a plethora of malformations of the vasculature.
- In C166 mouse embryonic endothelial cells, exposure to VDCs inhibited tube formation.
- By computational toxicity, putative molecular targets for the compounds were predicted.

To identify vascular disruptor compounds (VDCs), this study utilized an in vivo zebrafish embryo vascular model in conjunction with a mouse endothelial cell model to screen a subset of the U.S. Environmental Protection Agency (EPA) ToxCast Phase I chemical inventory. In zebrafish, 161 compounds were screened and 34 were identified by visual inspection as VDCs, of which 28 were confirmed as VDCs by quantitative image analysis. Testing of the zebrafish VDCs for their capacity to inhibit endothelial tube formation in the murine yolk-sac-derived endothelial cell line C166 identified 22 compounds that both disrupted zebrafish vascular development and murine endothelial in vitro tubulogenesis. Putative molecular targets for the VDCs were predicted using EPA's Toxicological Prioritization Index tool and a VDC signature based on a proposed adverse outcome pathway for developmental vascular toxicity. In conclusion, our screening approach identified 22 novel VDCs, some of which were active at nanomolar concentrations